Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Congenital heart disease (CHD) is a risk factor for premature cardiovascular complications. Great advances have occurred in the past years leading to the identification of several genes essential for proper cardiac formation such as GATA4/5/6 mutated in some individuals with CHD. GATA6 is a zinc finger transcription factor whose presence is crucial for early embryonic development. GATA6 is expressed in many cell types of the heart including myocardial, endocardial, neural crest, and vascular smooth muscle. In human, mutations in GATA6 result in variable cardiac phenotypes. The objective of this thesis was to determine the roles that GATA6 play in the different cell types of the heart and to elucidate the molecular basis of the cardiac defects associated with Gata6 haploinsufficiency. For this, a combination of cell and molecular techniques were used in vitro and in vivo. First, we show that Gata6 heterozygozity leads to RL-type bicuspid aortic valve (BAV)- the most common CHD affecting 2% of the population. GATA6-dependent BAV is the result of disruption of valve remodeling and extracellular matrix composition in Gata6 haploinsufficient mice. Cell-specific inactivation of one Gata6 allele from Isl-1 positive cells, but not from endothelial or neural crest cells, recapitulates the phenotype of Gata6 heterozygous mice revealing an essential role for GATA6 in secondary heart field myocytes during valvulogenesis. We further uncovered a role for GATA6 as an important regulator of the cardiac conduction system and revealed that GATA6 expression regulates the activity of the cardiac pacemaker. GATA6 exerts its role via regulation of the cross-talk among the different cell types of the SAN. Lastly, some CHDs are characterized by abnormalities of both the limbs and the heart such as the Holt Oram syndrome (caused by mutation in TBX5 transcription factor). The molecular basis for limb-heart defects remain poorly understood. In the course of this work, we discovered that Gata6 haploinsufficiency resulted in a partially penetrant polysyndactyly (extra digits fused together) phenotype. Together, the data provide novel molecular and cellular insight into GATA6 role in normal and pathologic heat development. Our results also suggest that GATA6 should be added to the list of genes whose mutations are potentially associated with heart and limb abnormalities. Better knowledge of the molecular basis of CHD is a prerequisite for the development of diagnostic and therapeutic strategies to improve care of individuals with congenital heart disease.

Bakgrund: Aortaaneurysm är en vidgning på stora kroppspulsådern, en asymtomatisk diagnos som kan blir livshotande om den brister. Aneurysm kan repareras med antingen öppen kirurgi eller endoskopiskt. Män är majoriteten av dessa patienter och rökning, hjärtkärlsjukdomar samt hög ålder utgör riskfaktorer. Syfte: Syftet med litteraturöversikten var att beskriva personers erfarenheter av att leva med ett aortaaneurysm. Metod: Designen är kvalitativ litteraturöversikt med induktiv ansats. Resultatartiklar söktes fram på databaserna CINAHL, PubMed och PsychInfo med hjälp av relevanta sökord för ämnet. Även manuella sökningar gjordes. De framtagna artiklarna lästes med hjälp Fribergs 5-stegsmodell och analyserades utifrån Graneheim och Lundmans kvalitativa innehållsanalys. Analysen resulterade i tre huvudkategorier och sju subkategorier. Resultat: Vägledning i att ha levt med aortaaneurysm, Emotionella aspekter av att ha levt med aortaaneurysm och Livet och vardagen med aortaaneurysm var de tre huvudkategorierna som framkom från analysen, och subkategorierna Information från vården, Kunskap kring diagnosen, Rädsla för diagnosen, Tankar kring döden, En framtid trots diagnos, Mötet med vården samt Begränsningar i vardagen. Information var det som var mest påtagligt och som under tidens gång visade sig kunna påverka övriga subkategorier både positivt och negativt beroende på mängd, leveranssätt och tidpunkt.  Slutsats: Genom denna litteraturöversikt visade sig erfarenheterna variera och dessa var individuella beroende på var i livet deltagaren befann sig och hur livet i övrigt var för deltagaren. Ytterligare studier behövs för att ta fram ett mer personcentrerat och individuellt tillmötesgående för personer med aortaaneurysm. / Background: Aortic aneurysm is a dilation of the aorta, an asymptomatic diagnosis that can become life-threatening if it burst. Aneurysms can be repaired with either open surgery or endoscopically. The majority of patients are men, and smoking, cardiovascular disease and old age are risk factors. Aim: The aim of the literature review was to describe people´s experiences of living with an aortic aneurysm. Method: The design is a qualitative literature review with an inductive approach. Result articles were searched on the databases CINAHL, PubMed and PsychInfo using relevant keywords for the topic. Manual searches were also performed. The produced articles were read using Friberg's 5-step model and analyzed on the basis of Graneheim and Lundman's qualitative content analysis. The analysis resulted in three main categories being selected with seven subcategories. Results:  Guidance in lived aortic aneurysm, Emotional aspects in lived aortic aneurysm and Life and daily living with aortic aneurysm were the three main categories which emerged in our analysis. With the subcategories Information from the healthcare, Knowledge about the diagnosis, Fear of the diagnosis, Thoughts about death, Future despite the diagnosis, Meeting the healthcare and Obstacles in everyday life. Information was what was most noticeable and over time, it turned out to be able to influence other subcategories both positively and negatively depending on quantity, delivery method and time. Conclusion: Through this literature review, the experiences turned out to be varied and these were individual depending on where in life the participant was and how life in general was for the participant. Further studies are needed to develop a more person-centred and individualized approach for people with aortic aneurysm.

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Aortic stenosis is a disease that causes a narrowing of the aortic valve opening. It is a disease that can be found in more than 2% of the elderly population. In the past, the only effective treatment has been open heart valve replacement, but in the last decade it has become possible to also treat aortic stenosis through a percutaneous procedure known as transcatheter aortic valve replacement. An implant-carrying catheter is led up to the patient’s heart where the implant is deployed. Sizing, positioning, and orientation of the implant are important considerations in transcatheter aortic valve replacement. Purpose: The purpose was to investigate the feasibility and potential features of a virtual heart valve implant system and how the available assets at the Medical Devices Center and its collaborators could create a useful tool for virtual transcatheter aortic valve implant selection, sizing, positioning, and orientation. Implementation: Challenges with transcatheter aortic valve replacement among clinicians and engineers were identified. A virtual heart valve implant system was proposed as a solution. The idea space for a virtual heart valve implant system was explored and structured systematically with a new approach called the idea connection tree method. A proof of concept prototype with a 3D model of an aorta and an implant in three different sizes was created as a way to gauge if there is user value in a virtual heart valve implant system. Result & Conclusion: For the proposed solution of a virtual heart valve implant system, 43 unique ideas were generated. Three main branches of ideas were identified: Design, simulation, and a database branch. It was estimated that the simulation branch would provide the most user value for comparatively low work effort. The proof of concept prototype showed that it was possible to visually evaluate the interference produced by different sized implants inside a 3D model of an aorta on a virtual reality system. / Aortastenos är en sjukdom som orsakar förträngning av aortaklafföppningen. Det är en sjukdom som återfinns hos mer än 2% av den äldre befolkningen. Tidigare har den enda effektiva behandlingen inneburit hjärtklaffersättning med öppen hjärtkirurgi, men under det senaste decenniet har det blivit möjligt att också behandla aortastenos med en perkutär procedur i form av kateterburen implantation av aortaklaff. En kateter som bär på en aortaklaffprotes förs fram till patientens hjärta där protesen sedan utplaceras. Dimensionering, positionering och orientering av protesen är viktiga överväganden i kateterburen implantation av aortaklaff. Syfte: Syftet är att undersöka genomförbarheten och potentiella funktioner hos ett virtuellt implanteringssystem för hjärtklaffproteser och hur tillgångarna hos Medical Devices Center och deras samarbetspartners kan skapa ett användbart verktyg för virtuell dimensionering, positionering samt orientering av kateterburna hjärtklaffproteser. Implementering: Utmaningar med kateterburen hjärtklaffimplantering bland kliniker och ingenjörer identifierades. Ett virtuellt implanteringssystem för hjärtklaffproteser föreslogs som en lösning. Idérymden utforskades och strukturerades systematiskt med en ny metod kallad för idésambandsträd-metoden. En konceptprototyp med 3D modeller på en aorta och en protes i tre olika storlekar skapades för att uppskatta om det finns användarvärde i ett virtuellt implanteringssystem för hjärtklaffproteser. Resultat & Slutsats: För den föreslagna lösningen av ett virtuellt implanteringssystem för hjärtklaffproteser genererades 43 unika idéer. Tre huvudsakliga grenar av idéer identifierades: Konstruering, simulering och en databasgren. Det uppskattades att simuleringsgrenen skulle kunna förse den största mängden användarvärde för en förhållandevis låg arbetsinsats. Konceptprototypen visade att det var möjligt att visuellt utvärdera interferensen av olika protesstorlekar inuti en 3D model av en aorta med hjälp av ett virtual reality system.

Aneurysms of the aortic root and ascending aorta often require surgical correction. Currently, two common alternatives exist: The Bentall procedure has traditionally been used successfully for many decades, utilising an aortic valve prosthesis to replace the aortic valve and a conduit to replace the aneurysmic aorta. The more recent approach has been to reimplant suitable aortic valves utilising a dacron graft as well as replacing the affected aortic segment. The most widely used technique thereof is the David procedure. The decision for either operation depends greatly on patient circumstance and preference, as well as the recommendation of the operating surgeon. This is due to the associated features and disadvantages of the procedures at hand that make the careful choice of technique vital. Previous research has shown promising results for the equivalence, if not superiority, of the David procedure in certain patient groups, as well as in comparison to the Bentall procedure overall. At the same time, there are concerns about the David approach regarding the durability, perioperative risk, and long-term outcomes, among others. Regardless, avoidance of anticoagulation postoperatively has made it an attractive choice for patients who do not want to or cannot receive anticoagulants. While the David procedure has shown these beneficial properties, it has been widely limited to cases where the aortic valve is deemed suitable. Over the last decade, several studies have assessed the usage of David procedure for cases that did not previously seem to be a fit, such as patients with bicuspid aortic valves, who are now deemed suitable. With the David procedure becoming more widely applied and the application of the operation being extended, the question arises, whether the Bentall procedure remains the gold standard for correction of aortic root pathology. Several studies have been conducted over the years, but because cases are comparatively few, evidence is still lacking. For this, we conducted a study into the short and long-term outcomes of patients who underwent either Bentall or David procedures at the Leipzig Heart Centre between 2000 and 2015. Pre-operative, operative and post-operative data was gathered, and a follow-up was conducted through questionnaires, reports by physicians and telephone surveys. Statistical analysis was performed to gain data on perioperative mortality, adverse outcomes and long-term effects, such as bleeding incidents, reoperation rates and overall mortality, among others. This resulted in two publications that form the basis of this dissertation: Publication A sought to compare the outcomes of David cases with those who received correction with the Bentall procedure, including both mechanical valve prostheses and biological replacements. Publication B compared David cases to biological Bentall replacements. This subgroup analysis was done because both procedures avoid long term-anticoagulation. We found that both the David and Bentall operation had excellent early and long-term results, with comparable outcomes for early and late mortality among others. Furthermore, we did not see an increased risk of reoperation for the David procedure during our observational period. We recorded a higher incidence of serious bleeding events in the Bentall group (Publication A). The comparison of bioprosthetic Bentall cases to the David group showed equivalent outcomes for both procedures without significant difference in endpoints. While patient preferences and circumstances should still be considered, our investigations showed clear advantages for the David procedure in the analysed patient group. We concluded that the David operation is the preferable operation in patients with appropriate pathoanatomy, because long-term complications associated with prosthetic heart valves remain a major concern and it has shown to mitigate said complications.

BACKGROUND: Sirtuin-1 (SirT1) is a NAD+-dependent deacetylase essential for maintaining the structure and function of the vasculature. Reduced SirT1 expression and activity has been correlated with the development of vascular diseases, mainly attributed to loss of SirT1’s anti-oxidant and anti-inflammatory beneficial effects. We previously found that deletion of vascular smooth muscle (VSM) SirT1 in mice is associated with increased matrix metalloproteinases (MMPs) and the subsequent development of aortic dissections or ruptures in response to the hypertensive peptide angiotensin II. Based on these previous findings, we hypothesize that loss of SirT1 activity is involved in the pathogenesis of AA. SirT1 is a stress response gene, its deacetylase activity can be impaired by excessive oxidative stress. We postulate that mutating three cysteine residues in SirT1’s catalytic domain can prevent its inactivation by oxidative insults and protect against AA and other vascular diseases. OBJECTIVES: assess the role of SirT1 in a genetic mouse model of Marfan Syndrome that develops AA; (2) Determine design and optimize an enzyme-based colorimetric ELISA to determine SirT1 activity in mouse VSM cells and aortas; (3) Produce an adeno-associated virus (AAV) expressing an oxidant-resistant triple mutant SirT1 in VSM cells that has the potential to mitigate the downstream outcomes derived from alterations in SirT1 activity, such as MMPs activation and development of AA in mgR-/- mice. METHODS: mgR-/- and littermate mgR+/+ (WT) mice aortas and VSM cells were cultured in conditioned medium and the activity of released MMPs was determined by in-gel zymography. For the development of the SirT1 activity assay, we designed a multi-step sandwich ELISA that captures a biotin- and FLAG-tagged acetylated p53 peptide, used as SirT1 deacetylase substrate. Amounts of acetylated and total p53 peptide were sequentially detected with antibodies and colorimetric substrates as index of SirT1 deacetylase activity. AAVs expressing a control or triple mutant SirT1 (3M) were produced in HEK293T cells; VSM cells were then infected with control or 3M AAV and SirT1 protein expression levels were measured by Western Blot. RESULTS: MMPs activity is increased in aortas and VSMC of mgR-/- mice; the first stage of optimization of the SirT1 activity assay successfully defined the assay conditions and experimental design, and it is ready to be optimized with mgR-/- cell and tissue samples; our novel control and SirT1 triple mutant AAVs were produced and successfully overexpressed in VSM cells. / 2024-03-14T00:00:00Z

<div><div><div><p>The aorta has many complex features including valve and vessel wall geometry, blood flow, and wall composition. Diseases such as aortic aneurysms and aortic valve lesions affect vessel function and may even lead to rupture, which can be fatal. However, current clinical diagnoses of aortopathies mainly rely on simple parameters such as diameter and growth rate. To better understand aortopathies and ultimately improve patient diagnoses and treatments, it is important to investigate disease progression as well as the effect of vessel wall composition changes and hemodynamic forces on aortic biomechanics, such as strain and wall shear stress distribution. Preclinical research using small animals allows for disease progression to be studied while controlling outside factors. The next important step is to apply the methods used in the preclinical studies to human patient data. Both preclinical and clinical studies often focus on noninvasive, patient-specific methods for further characterizing the biomechanics of the aorta using advanced techniques such as 4D flow magnetic resonance imaging, 4D ultrasound, computational fluid dynamics (CFD), and fluid structure interaction (FSI) modeling. Yet the challenge of bridging these research techniques to a clinical setting remains. Factors such as financial costs, acquisition time, and ease of analysis must be considered. Therefore, the following document highlights two specific aims to extend our knowledge about the effects of aneurysms and aortic valve lesions. We will 1) characterize the regional effects of murine abdominal aortic aneurysms on strain over time, and 2) use CFD and FSI to simulate the hemodynamic effects on the thoracic aorta using both murine and human patient imaging data. Conducting research using clinically translatable methods of biomechanical characterization that consider the complexity of the aorta on a patient-specific basis will contribute to our understanding and lead to better patient outcomes.</p></div></div></div>

Addition of lysophosphatidic acid (LPA) to rat aorta-derived endothelial cells significantly induced preproendothelin-1 (preproET-1) mRNA expression. PreproET-1 mRNA levels reached a plateau within 1 h after the addition of 0.5 μM LPA and declined after 2 h. The induction was superinduced by cycloheximide and was blocked by actinomycin D. Suramin, an LPA receptor antagonist, abolished the induction of preproET-1 mRNA by LPA. Protein kinase C inhibitors, H7 and bisindolylmaleimide, were able to block the induction. Transient transfection experiment revealed that the elevated preproET-1 mRNA was a result of the activation of ET-1 gene activity. Electrophoretic mobility shift assay revealed that LPA stimulated the binding of AP-1. The secreted level of ET-1 was elevated 2.3-fold after 12 h of stimulation with LPA. Our results suggest that the upregulation of preproET-1 by LPA may serve to augment and prolong the vasoconstriction action of LPA.

Objective: Studies have shown that iodinated radiocontrast use is associated with acute renal failure especially in the presence of chronic kidney disease and multiple factors modulate this risk. The purpose of this meta-analysis is to compare the incidence of renal failure requiring hemodialysis between transfemoral (TF) and transapical (TA) transcatheter aortic valve replacement using the Edwards valve. Methods: The PubMed database was searched from January 2000 through December 2014. A total of 10 studies (n = 2,459) comparing TF (n = 1,268) and TA (n = 1,191) TAVR procedures using the Edwards valve were included. Variables of interest were baseline logistic EuroSCORE, prevalence of diabetes mellitus, hypertension, peripheral arterial disease, chronic kidney disease and amount of contrast used. The primary endpoint was incidence of renal failure requiring hemodialysis. The odds ratio and 95% CI were computed and P < 0.05 was considered as the level of significance. Results: The logistic EuroSCORE was significantly higher in TA compared to TF (P = 0.001) TAVR. The amount of contrast (mL) used was significantly higher in the TF group compared to the TA group (mean difference: 36.9, CI: 25.7-48.1, P < 0.001). The incidence of hemodialysis following the procedure was significantly higher in the TA group compared to TF group (odds ratio = 4.3, CI: 2.4-7.8, P < 0.00001). Conclusions: This meta-analysis suggests that despite the lower amount of contrast used in TA-TAVR, the incidence of renal failure requiring hemodialysis was higher with the Edwards valve. This suggests that the incidence of renal failure requiring hemodialysis after TAVR is associated with baseline comorbidities in the TA-TAVR group rather than the volume of contrast used.

Objectives: In patients with severe aortic stenosis who are at high risk for surgery, transcatheter aortic valve replacement (TAVR) has emerged as an alternative procedure using EV or CV. The objective of this meta-analysis is to compare 1-year mortality and major adverse cardiovascular and cerebrovascular events (MACCE) between Edwards valve (EV) and Medtronic CoreValve (CV). Methods: PubMed and the Cochrane Center Register of Controlled Trials were searched through December 2014. Twenty seven studies (n = 12,249) comparing TAVR procedure that used EV (n = 5745) and CV (n = 6504) were included. End points were procedural success rates, post-procedural mortality, myocardial infarction (MI), stroke, major bleeding, major vascular complications, incidence of new permanent pacemaker (PPM) placement and new left bundle branch block (LBBB). The odds ratio (OR) with 95% confidence interval (CI) was computed and p < 0.05 was considered for significance. Results: There were no significant differences between EV and CV for post-procedural in-hospital, 30-day and 1-year all-cause mortality rates (p = 0.53, 0.33 and 0.94 respectively), cardiovascular mortality (p = 0.61), stroke (p = 0.54), major bleeding (p = 0.25) and major vascular complications (p = 0.27). MI was significantly lower with EV compared to CV (OR: 0.56, CI: 0.35-0.89, p = 0.01). Placement of new PPM and new onset LBBB were significantly higher in CV compared to EV (OR: 3.35, CI: 2.96-3.79, p < 0.00001 and OR: 6.55, CI: 4.76-9.03, p < 0.00001 respectively). Conclusions: The results of our meta-analysis suggest that TAVR procedure using CV may be associated with a higher incidence of MI, new PPM placement, and new onset LBBB compared to EV. However, the type of valve placed does not affect mortality.